Novel derivatives of 2h, 8h-benzo-[1, 2-e&#39;, 5, 4-e&#39;]-bis-[1, 2, 4]-thiadiazine-1, 1, 9, 9-tetraoxide



3,242,172 NOVEL DERIVATIVES F 2H,8H-BENZO-[1,2-e,5,

4-e]-BIS-[1,2,4]-THIADIAZINE 1,1,9,9 TETRA- OXIDE John G. Topliss,Bloomfield, N.J., assignor to Schermg Corporation, Bloomfield, N.J., acorporation of New Jerse No l rawiug. Filed Aug. 14, 1963, Ser. No.301,949 9 Claims. (Cl. 260-243) This invention relates to novelcompounds having therapeutic activity and to processes for manufacturingthe same.

More particularly this invention relates to novel derivatives of2H,8H,-benzo-[1,2-e:5,4e']-bis-[1,2,4]-thiadiazinel,l,9,9-tetraoxidewhich exhibit mild tranquilizing prop erties.

The compounds of the present invention may be represented as having thestructural formula:

and the non-toxic alkali metal salts thereof, wherein X rep-resentslower alkyl, and halogen, and R and R each represent hydrogen, loweralkyl, phenyl and benzyl.

It is readily apparent to one skilled in the art to which this inventionrelates, that the molecules may exist in more than one tautomeric form.In one thiadiazine-1,ldioxide moiety the double bond may exist betweenthe 2- and the 3-tposi-tion atoms, or it may exist between the 3- and 4position atoms; in the other thiadiazine-1,l-dioxide moiety the doublebond may exist between the 6- and the 7'position atoms, or it may existbetween the 7- and 8-position atoms. Thus, although only one tautomericform is depicted within this application it is to be understood thatsuch tautomers are equivalent entities and therefore all possibletautomers are contemplated as being within the scope of this invention.

The novel compounds of this invention are useful, as mild tranquilizingagents characterized by locomotor depression, ptosis, increased sleepand decreased alertness, and in their effects are suggestive ofimipramine like action. Thus, these agents may be useful in thetreatment of behavioral disturbances such as those presently treated byphenothiazine tranquilizers.

The compounds can be administered in therapeutic dosages in conventionalvehicles as in the form of a tablet or a capsule as these compounds areefiective upon oral administration as well as upon injection. As thecompounds of this invention also are readily soluble in a. dilutealkaline medium or in polyethylene glycol solutions, injectablesolutions can be prepared by dissolving the desired compound in theselected medium to which preservatives can be added if desired.

Exemplary of the various radicals symbolized by either X, R and R ofstructural Formula I are: for lower alkyl, methyl, ethyl, n-propyl,isopropyl, cyclopro-pyl and such other straight, branched and cyclizedsaturated lower aliphatic hydrocarbyls, as well as suchequivalently-acting 3,242,172 Patented Mar. 22, I966 radicals as thehalogenoalkyls such as monochloromethyl, dichloromethyl,trichloromethyl, trifiuoromethyl, monochloroe-thyl and the like; forhalogen, chlorine, bromine, fluorine, and iodine; for phenyl, and suchequivalently-acting radicals as the ortho, meta, and parachlorophenyl,methoxyphenyl, methylphenyl and the like, and for benzyl, benzyl andsuch equivalently-acting radicals as the ortho, meta, andpara-chlorovbenzyl, rnethoxybenzyl, methy'lbenzyl and the like, and suchother radicals as phenethyl, and the like.

In general, the compounds of this invention may be prepared from anappropriately substituted 6-a mino-2H,-1,2,44benzothiadiazine-7-sulfonam-ide 1,1-dioxide (II) with a reactantsuch as an ortho ester, R-C(OR) a carboxylic acid, RCOO-H or aderivative thereof such as the corresponding acid halide, anhydride,amide and simple lower alkyl esters, or other chemically equivalentcompounds which, under the reaction conditions, are convertiblethereunto. For each of these reactants, R is as defined above, and Rrepresents lower alkyl. In these reactions all reactants are essentiallyequivalent in ultimately producing the end product. Thus, the reactionof 6- mino-S-methyl 2H 1,2,4 benzothiadiazine-7-sulfon--amide-l,l-dioxide with either ethyl ortho-acetate,u-methoxy-ac'etaldehyde diethyl acetal, acetic acid, acetyl chloride,acetic anhydride, or ethyl acetate will ultimately result in theformation of 5,7-dimethyl-2H,8H-benzo- [1,2-e:5,4-e] bis[l,2.4]-thiadiazine-l,.1,9,9-tetraoxide. It is understood that minorvariations in reaction conditions may be necessary to effect thetransformation, said variations dependent upon the nature of thereactant as set forth below.

The novel2H,8H-benzto-[l,2-e:5,4-e']-bis-[1,2,41-thiadiazine-l,1,=9,9-tetraoxidecompounds (I) are thus prepared by heating 6amin'o-2H-l,2,4-benzlothiadiazine-7- sulfonamide 1,1-dioxide (II) withreactants such as the above mentioned ortho esters, carboxylic acids,acid halides and acid anhydrides and acetals. When the carboxylic acids,acid halides or acid anhydrides are used as reactants, a catalyst isusually necessary in order to directly produce the appropriate2H,8H-benzo-[l,2-e:5,- 4e'] bis-[l,2,4]4thiadiazine l,l,9,9-tetraoxide(I) without first isolating intermediary substances, although in certaininstances the product can be directly formed by heating the reactants atmuch higher temperatures without the use of a catalyst. When used, thecatalyst may be basic, such as the alkali metal salts of thecorresponding oa-rboxylic acids, a tertiary amine such as pyridine,tpicoline, or lutidine, or the catalyst may be acidic in nature such asfor example, perchloric acid.

Wlhen reacting the 6-amino-2H-1,2,44benzothiadiazine- 7-sulfon'amide1,1-dioxide (II) starting material with an ortho ester, the reaction isgenerally carried out at above room temperatures.

In the absence of a solvent, the temperature range is from about 40 C.to the boiling point of the particular ortho ester, although atemperature range of about C. is preferred. it the reaction is carriedout in the presence of an inert organic solvent, the temperature isusually maintained at about the reflux temperature of the reactionmixture. Sol-vents such as dioxane or dimethylene glycol dimethyl etherare preferred but other suit able nonreactive solvents may also he used.

h a Y- a d reactant, the reaction is pr f add water to the residualmaterial. Collect the crude ably eifected with catalysis, underpressure, and with inproduct by filtration, wash with water and air dryto give creased temperatures in the range of about 130200 C., 6.05 g. ofa discolored solid. Recrystallize from methalthough it is preferred touse tem peratures between anol to yield 4.3 g. of5-chloro-4,6-diamino-m-benzeneabout 160 and 170 C. 5 disulfonamide.

With an a id halid or a id anhydride rea tant, such Dissolve 7-1 g. of5-chloro-4,6-diamir1o-m-benzenedisul reactant i excess is heated i the6-\arminQ-2H-7-su1- fonamide in a hot mixture of 30 ml. of ethylorthoacetate 'fonam'ide-1,2,4-benzothiadiazine-1,l-dioxide startingmaand of 2-m-ethoxyethanol and reflux the resulting terial (II) in thepresence of on of the above d ib d solution for 12 hours. Filter thecooled reaction mixture catalysts. and wash the solid product withmethanol and air dry The afore-described chemically equivalentpreparations to Yield of 5"Ch10r0-3,7-di1T1Bthy1-2H,8114361110 areillustrated as follows: [1,2 e:5,4-e]bis-[1,2,4]-thiadiazine-1,1,9,9-tetraoxide,

l N HzN (a) Remotes,

NH heat l X HzNOzS l 32 (b) C2H5OOH2CH(OC2H5)2 R /N\ /N\ R heat HN NH(0) RCOOH heat \S/ \s/ or O: 02 01 catalyst (RCOMO In the foregoingscheme, X, R and R are as hereinwhich is purified by recrystallizationfrom a dimethyformabove defined. The ortho ester reactant in A is shownas amide-water mixture.

being an ethyl ester, however, it is understood that other EXAMPLE 2common lower alkyl esters may be simllarly employed without changing thefinal product, since the alkoxy groups 5,7-dif1wi/1yl-2H ,8H "Z 2 areeliminated during the reaction. The acetal reactant 35ihiadiflline-l.1,9,946lrl10xid6 (in A(b)) is shown as ethoxyacetaldehydediethyl acetal. Heat a mixture of 51) g. of 6 amin0 5 methy1 2H 1,2,4 Itis understood that any lower alkyl acetal h be usedbenzothiadiazine-7-sulfam ideal,l-dioxide, 50 ml. of ethyl or any loweralkoxy h m be employed In Plac? orthoacetate and 150 ml. ofZ-methoxyethanol at the reflux the ethoxy groups dehlcted Slhce thesegroups are ehml' temperature of the reaction-mixture for 12 hours.Filter hated dhnhg reachoh' The cohtrohlhg feature of the 40 the cooledreaction mixture, wash the solid product With h rehctaht 15 thestructure of the h atom and methanol and recrystallize fromdimethylformamide-water its substituents. For example, by employingot-ethoxyto give 5 7 dimethy1 2H 8H benZo [12 e:5 propionaldehydezacetal, the product (I) would have a 3- 4] thiadiazine l 1 9 9tetgaoxide ethyl substituent.

The substituted 6-amino-2H-l,2,4-benzothiadiaZine-7- EXAMPLE 3sulfonamide1,1-dioxide starting material may be prepared I by proceduresset forth in the F. C. Novello US. Patent 5 chlom 6 3; 7 522 25 525 2 5;5 :323 e 1 his No. 2,910,474 with, of course, proper modification in theNovello starting materials so as to take into consideration Heat amixture of 5 of H 3, h X d i t d b it tbenzothiadiazine-7-sulfonamide-1,l-dioxide, ml. of

For the synthesis f compounds f f l I wherein R 50 ethylorthochloroacetate and 150 ml. of Z-methoxyethanol and R are the same,alternative methods are available. at reflux temperature for 12 hollfs-C001 and filtfir i116 These methods consist in converting a4,6-diamino-m-benreaction mixture, Wash the Solid Product With methanolzenedisulfonamide i t a compound of F l I b and recrystallize the solidfrom dimethylformamide-water methods generally used in converting ano-sulfamylaniline to givfi the Product of this p into a1,2,4-benzothiadiazine ring system. For example, EXAMPLE 4 a mixtureconsisting of ethyl orthoacetate and S-chloro-4,6-diamino-m-benzenedisulfonamide in a non-reactive y Z solvent may beheated at its reflux temperature to produce thiadiazine-],1,9,9- r wxi gg l iii ;gil lghihi ggigg gigi H315 Dissolve 5 .0 g. of 5methyl-4,6-diamino-m-benzenedisulj preparation i compounds'embraced yformula fonamrde in a hot mlxture containing 25 ml. of ethyl or- I ismore fully described in the following exam les It thoacetatet and ofZmethoxyethanol and reflux is to be understood however that the examples:re illusthe r-esultm-g sohmon for 12 h9urs' Cool and filter the trativof th Com b e i need b f d reaction mlxture, Wash the solid product withmethanol 3 e p s m y 15 lhveh an and recrystallize fromdrmethylformamide-water to give of the methods for their preparation andare, therefore, the product ofthis example not to be construed aslimiting the invention to the particular compounds or methodsspecifically described. EXAMPLE 5 EXAMPLE 15-methyl-3-phenyl-2H,8H-benz0-[1,2-e:5,4-e']-bis-[1,2,4]- 5-chl0r0-3,7-dimethyl-2H ,8H -benz0- [1 ,2-e:5,4-e']bis- 7O thiadia ine-J,1 ,9,9tetra0xide [1 24]thladmzmeJJppdetmoxlde Heat a mixture of 5.0 g.of 6-amino-5-methyl-2H-1,2,4- Heat a mixture of 9.45 g. of4-amino-5,6-dichlorobenbenzothiadiazine-7-sulfonamide-1,l-dioxide, 5.0g. of benzene-m-disulfonamide, 250 ml. of ethanol and 50 g. of zoylchloride and 50 ml. of dimethylformamide on the ammonia in an autoclavefor 5 hours at 170-180 C. steam bath for3 hours. Cool the reactionmixture, dilute Evaporate off the solvent and the excess of ammonia andwith ml. of water and filter oil the precipitated 6-benzamide 5 methyl2H 1,2,4-b-enzothiadiazine-7-sulfonan1idel,l-dioxide. Melt the lattersubstance and keep in the molten state for 5 minutes. Cool andrecrystallize the residue from dimethyliormamide-Water to give theproduct of this example.

EXAMPLE 6 EXAh PLE 7 Heat a mixture of 5.0 g. of6-amino-5ch1oro-2I-I,1,2,4- benzothiadiazine-7-sulfonamide-1,l-dioxide,5.0 g. of phenylacetyl chloride and 50 m1. of dimethyformamide on thesteam bath for 3 hours. Cool the reaction mixture, dilute with 150 ml.of Water and filter off the precipitated 5ehloro-S-(ct-phenylacetarnido)-2-H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide.Melt the latter substance and keep in the molten state for 5 minutes.Cool and recrystallize the residue from dimethylformamide-water to givethe product of this example.

EXAMPLE 8 Dissolve 7.1 g. of 5-chloro-4,6-diamino-m-benzenedisulfonamide in a hot mixture of 30 ml. of ethyl orthoformate and 75ml. of Z-rnethoxyethanol and reflux the resulting solution for 12 hours.Filter the cooled reaction mixture and wash the solid product withmethanol and air dry to yield a product of this example.

EXAMPLE 9 S-mclhyl-2H,8H-benz,ol,2-e:5,4-e] -bis- [1,2,4] Ziriadiazined,1 ,9,9-te traoxide Heat a mixture of 5.0 g. of6-amino-5-methyl-2H-1,2,4-

benzothiadiazine-7-sulfonamide-1,l-dioxide, 50 m1. of

ethyl orthoformate and ml. of Z-methoxyethanol at the reflux temperatureof the reaction mixture for 12 hours. Filter the cooled reactionmixture, wash the solid product with methanol, and recrystallize fromdimethylformamide to give S-methyl 2H,8H-benzo-[1,2-e:5,4-e]-bis-[1,2,4j-thiadiazine l,1,9,9-tetraoxide.

I claim:

1. A compound selected from the group consisting of compounds having thestructural formula:

and the non-toxic acid addition salts thereof, wherein X is a memberselected from the group consisting of lower alkyl and halogen, and R andR each represent a member selected from the group consisting ofhydrogen, lower alkyl, phenyl and benzyl.

2. A compound of claim 1 where R and R each represent lower alliyl and Xrepresents halogen.

3. A compound of claim 1 wherein R and R each represent hydrogen and Xrepresents lower alkyl.

4. A compound of claim 1 wherein R is hydrogen, X is halogen and R islower alkyl.

5. 5 chloro 3,7-dimethyl-2H,8H-benzo-[1,2-e:5,4-e]-bis-[1,2,4]-thiadiazine'1,1,9,9-tetraoxide.

6. 5,7 dimethyl-2H,8H-benzo-[1,2,-e:5,4-e']-bis-[1,2,4]-thiadiazine-1,1,9,9-tetraoxide.

7. 3,5,7 trimethyl 2H,8H benzo-[l,2,-e:5,4-e']-bis- [1,2,4]-thiadiazine-1,1,9,9-tetraoxide.

8. 5 methyl-3-phenyl-2H,8H-benzo-[1,2-e:5,4-e']-bis-[1,2,4-]-thiadiazine-1,1,9,9-tetraoxide.

9. 3 benzyl 5-chloro-2l-L8H-benzo [1,2-e:5,4-e]bis- [1,2,4]-thiadiazine-1, 1 ,9,9-tetraoxide.

References Cited by the Examiner UNITED STATES PATENTS 2,910,475 10/1959Novello 260243 2,965,656 12/1960 Novello 260-243 3,063,995 11/1962Bernstein et a1 260-243 3,103,511 9/1963 Bernstein et al. 2602433,108,124 10/1963 Close 260-243 WALTER A. MODANCE, Primary Examiner.NICHOLAS S. RIZZO, Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THESTRUCTURAL FORMULA: